This invention relates to a topical ophthalmic formulation comprising a cyclosporin.
Cyclosporins represent a class of nonpolar cyclic oligopeptides having numerous pharmacological properties.
They are more particularly known for their immunosuppressive and antiinflammatory activity, and have also been described as being effective in enhancing or reestablishing tear secretion by the lachrymal gland in patients suffering from immune-mediated keratoconjunctivitis sicca.
Cyclosporins of natural origin which in their majority comprise cyclosporin A and in their minority the cyclosporins B to I can be obtained from the fungus Trichoderma polysporum. 
Like a large number of their analogs and isomers, cyclosporins can also be obtained by synthesis.
The cyclosporin most widely studied and used in pharmacy among the cyclosporins is cyclosporin A.
The activity of a cyclosporin and particularly of cyclosporin A in enhancing or reestablishing tear secretion by the lachrymal gland could be improved by improving absorption of cyclosporin in the lachrymal gland.
For reasons of the very low solubility of cyclosporins in water (20 to 30 μg/mL for cyclosporin A), it has been very difficult to prepare an ophthalmic composition containing a cyclosporin dissolved in an aqueous medium.
It is for this reason that the cyclosporins, known to be lipophilic, have mainly been used in oil-based formulations.
U.S. Pat. No. 4,839,342 describes a topical ophthalmic composition containing a cyclosporin, particularly cyclosporin A, and an excipient, to increase tear production in patients suffering from a lack of tears in the eyes because of a dysfunction of the lachrymal glands. The excipients specifically described are olive oil, peanut oil, castor oil, polyethoxylated castor oil, mineral oils, vaselines, dimethyl sulfoxide, an alcohol, liposomes, silicone oils or their mixtures.
FR-A-2,638,089 describes a topical ophthalmic composition which contains a cyclosporin as the active substance and a vegetable oil such as olive oil, peanut oil, castor oil, sesame oil and maize germ oil as the vehicle, as well as vaseline, to treat illnesses and immunological or inflammatory conditions affecting the eye, and particularly keratoconjunctivitis sicca (KCS) or dry eyes.
However, the oil-based topical ophthalmic formulations have disadvantages such as a disagreeable feeling in the eyes, or lead to dim-sightedness. The oils may moreover reinforce the dry-eye symptoms.
Oil-based topical ophthalmic formulations containing cyclosporin also are physically unstable, because the cyclosporins tend to undergo conformational changes and to precipitate.
These formulations moreover have a poor bioavailability and low eye tolerance, which shows by an irritation of the eyes.
For the purposes of minimizing certain of the above disadvantages such as discomfort in use, and of improving the bioavailability and tolerability of the formulation, it has been proposed in WO 95/31211 to reduce the amount of oil and disperse the oil phase in water so as to form an emulsion, which gave a topical ophthalmic formulation in the form of an emulsion based on water and on oil comprising a cyclosporin mixed with a triglyceride containing long-chain fatty acids such as castor oil and polysorbate 80. This formulation also contains an emulsifier, for instance Pemulen®.
For the purposes of eliminating the problems of cyclosporin precipitation while improving the bioavailability and tolerability of the formulation, an aqueous topical ophthalmic formulation has been proposed in U.S. Pat. No. 5,951,971 which is free of oil and comprises a cyclosporin in a concentration of 0.01 to 0.075% (w/v), water, and a surfactant in an amount of 0.1 to 3% (w/v) intended to improve the solubility of the cyclosporin in water and selected among the polyethoxylated fatty acid esters, the polyethoxylated alkylphenyl ethers, the polyethoxylated alkyl ethers and their mixtures. According to U.S. Pat. No. 5,951,971, it has been found that polysorbate 80, also known as Tween 80, is inappropriate as a surfactant, because it lacks an activity sufficiently high to solubilize a cyclosporin in the desired concentrations in water.